Tree-decomposable and underconstrained geometric constraint problems

Preprin

Retreatment with interferon-alpha and ribavirin in primary interferon-alpha non-responders with chronic hepatitis C

Background/Aims: Combination therapy with interferon-alpha (IFN-alpha) plus ribavirin is more efficacious than IFN-alpha monotherapy in previously untreated patients with chronic hepatitis C and patients with IFN-alpha relapse. Only limited data are available in IFN-alpha non-responders. In a multicenter trial we therefore evaluated the efficacy of combination therapy in IFN-alpha-resistant chronic hepatitis C. Methods: Eighty-two patients (mean age 46.8 years, 54 males, 28 females) with chronic hepatitis C were treated with IFN-alpha-2a (3 x 6 MIU/week) and ribavirin (14 mg/kg daily) for 12 weeks. Thereafter, treatment was continued only in virological responders (undetectable serum HCV RNA at week 12) with an IFN-alpha dose of 3 x 3 MIU/week and without ribavirin for a further 9 months. The primary study endpoint was an undetectable HCV RNA by RT-PCR at the end of the 24-week follow-up period. Results: After 12 weeks of combination therapy, an initial virological response was observed in 29 of 82 (35.4%) patients. Due to a high breakthrough rate after IFN-a dose reduction and ribavirin discontinuation, an end-of-treatment response was only achieved in 12 of 82 (14.6%) patients. After the follow-up period, a sustained virological response was observed in 8 of 82 (9.8%) patients. Infection with HCV genotype 3 was the only pretreatment parameter, which could predict a sustained response (HCV-1, 5%; HCV-3, 57.1%; p < 0.001). Conclusions: Despite a high initial response rate of 35.4%, sustained viral clearance was achieved only in 9.8% of the retreated primary IFN-alpha non-responders. Higher IFN-alpha induction and maintenance dose, as well as prolonged ribavirin treatment may possibly increase the virological response rates in non-responders, particularly in those infected by HCV-1

Ex vivo innate immune cytokine signature of enhanced risk of relapsing brucellosis.

BackgroundBrucellosis, a zoonotic infection caused by one of the Gram-negative intracellular bacteria of the Brucella genus, is an ongoing public health problem in Perú. While most patients who receive standard antibiotic treatment recover, 5-40% suffer a brucellosis relapse. In this study, we examined the ex vivo immune cytokine profiles of recovered patients with a history of acute and relapsing brucellosis.Methodology/principal findingsBlood was taken from healthy control donors, patients with a history of acute brucellosis, or patients with a history of relapsing brucellosis. Peripheral blood mononuclear cells were isolated and remained in culture without stimulation or were stimulated with a panel of toll-like receptor agonists or heat-killed Brucella melitensis (HKBM) isolates. Innate immune cytokine gene expression and protein secretion were measured by quantitative real-time polymerase chain reaction and a multiplex bead-based immunoassay, respectively. Acute and relapse patients demonstrated consistently elevated cytokine gene expression and secretion levels compared to controls. Notably, these include: basal and stimulus-induced expression of GM-CSF, TNF-α, and IFN-γ in response to LPS and HKBM; basal secretion of IL-6, IL-8, and TNF-α; and HKBM or Rev1-induced secretion of IL-1β, IL-2, GM-CSF, IFN-Υ, and TNF-α. Although acute and relapse patients were largely indistinguishable by their cytokine gene expression profiles, we identified a robust cytokine secretion signature that accurately discriminates acute from relapse patients. This signature consists of basal IL-6 secretion, IL-1β, IL-2, and TNF-α secretion in response to LPS and HKBM, and IFN-γ secretion in response to HKBM.Conclusions/significanceThis work demonstrates that informative cytokine variations in brucellosis patients can be detected using an ex vivo assay system and used to identify patients with differing infection histories. Targeted diagnosis of this signature may allow for better follow-up care of brucellosis patients through improved identification of patients at risk for relapse

T lymphocytes from patients with primary biliary cirrhosis produce reduced amounts of lymphotoxin, tumor necrosis factor and interferon-gamma upon mitogen stimulation

Primary biliary cirrhosis (PBC) is considered an autoimmune disease characterized by destruction of small intrahepatic bile ducts by lymphocytes. Altered functions of these lymphocytes might reflect an abnormal immune response leading to tissue damage. We investigated lymphokine secretion by mitogen-stimulated T lymphocytes from the liver biopsies of patients with PBC and for comparison also peripheral blood. In PBC, diminished synthesis of lymphotoxin (TNFP), tumor necrosis factor (TNFa) and interferon-y (IFIVy) was found both in T-cell lines from liver tissue and in peripheral blood. The reduction was most prominent for TNFP in early histological stages of PBC, and appeared to be a stable phenomenon when T cells were tested after long-term tissue culture. Analysis of mRNA levels indicates a possible link between reduced TNFP production and a defect in interleukin-2 transcription. The data suggest that diminished lymphokine production in patients with PBC may play ;In important role in the immanopathogenesis of this disease

Binding of Polarons and Atoms at Threshold

If the polaron coupling constant $\alpha$ is large enough, bipolarons or multi-polarons will form. When passing through the critical $\alpha_c$ from above, does the radius of the system simply get arbitrarily large or does it reach a maximum and then explodes? We prove that it is always the latter. We also prove the analogous statement for the Pekar-Tomasevich (PT) approximation to the energy, in which case there is a solution to the PT equation at $\alpha_c$. Similarly, we show that the same phenomenon occurs for atoms, e.g., helium, at the critical value of the nuclear charge. Our proofs rely only on energy estimates, not on a detailed analysis of the Schr\"odinger equation, and are very general. They use the fact that the Coulomb repulsion decays like $1/r$, while `uncertainty principle' localization energies decay more rapidly, as $1/r^2$.Comment: 19 page

Atrial Natriuretic Peptide Protects against Histamine-Induced Endothelial Barrier Dysfunction in Vivo

Endothelial barrier dysfunction is a hallmark of many severe pathologies, including sepsis or atherosclerosis. The cardiovascular hormone atrial natriuretic peptide (ANP) has increasingly been suggested to counteract endothelial leakage. Surprisingly, the precise in vivo relevance of these observations has never been evaluated. Thus, we aimed to clarify this issue and, moreover, to identify the permeability-controlling subcellular systems that are targeted by ANP. Histamine was used as important pro-inflammatory, permeability-increasing stimulus. Measurements of fluorescein isothiocyanate (FITC)-dextran extravasation from venules of the mouse cremaster muscle and rat hematocrit values were performed to judge changes of endothelial permeability in vivo. It is noteworthy that ANP strongly reduced the histamine-evoked endothelial barrier dysfunction in vivo. In vitro, ANP blocked the breakdown of transendothelial electrical resistance (TEER) induced by histamine. Moreover, as judged by immunocytochemistry and Western blot analysis, ANP inhibited changes of vascular endothelial (VE)-cadherin, β-catenin, and p120ctn morphology; VE-cadherin and myosin light chain 2 (MLC2) phosphorylation; and F-actin stress fiber formation. These changes seem to be predominantly mediated by the natriuretic peptide receptor (NPR)-A, but not by NPR-C. In summary, we revealed ANP as a potent endothelial barrier protecting agent in vivo and identified adherens junctions and the contractile apparatus as subcellular systems targeted by ANP. Thus, our study highlights ANP as an interesting pharmacological compound opening new therapeutic options for preventing endothelial leakage

Mammals of the Northern Great Plains

For the purposes of this book, the Northern Great Plains are defined as the states of Nebraska, North Dakota, and South Dakota. As a physiographic concept, the northern part of the great interior grasslands of North America is, of course, much broader in geographic extent than the Dakotas and Nebraska, but the three states lie in the heart of the region, and thus the title for this work seems appropriate. Our expectations in writing Mammals of the Northern Great Plains were to provide a comprehensive, yet semitechnical, treatmeat of free-living mammals that would prove useful to specialist and nonspecialist alike. The content and style therefore were developed in a way we hope will interest the inquiring high-school student, on the one hand, and provide a point of reference for the professional mammalogist on the other. Between these extremes, wildlife biologists, conservationists, environmental specialists, college students of vertebrate zoology, and others interested in mammalian natural history should find the present treatment useful for their needs as well. In the accounts that follow, species of each genus are listed in alphabetical order. Genera, families, and orders are arranged in conventional phylogenetic sequence, and treatment of these higher taxa is deliberately brief. Readers desiring more detail should consult the synopsis by Anderson and Jones (1967) for orders and families and that of Walker et al. (1964 and subsequent editions) for genera. Both scientific and vernacular names of species generally follow Jones, Carter, and Genoways (1979). Information in the accounts of species is organized under five headings: Name, Distribution, Description, Natural History, and Selected References. In the first section, comment is made on the derivation of the scientific name of the species; often, alternative vernacular names are provided. The section on distribution describes the general geographic and ecological range of a species. Subspecies (if recognized) are listed in this section. The geographic ranges of most species are mapped, based on the currently known distribution; the maps, however, are deliberately conservative, and additional fieldwork in various parts of the region certainly will extend the known limits of many mammals. In several cases where too few specimens of a species have been reported to allow the distribution in the tristate region to be shaded with confidence, only the actual localities of record are indicated

Transparency and adaptability aid in realigning the complexity of objectives, approaches, and systems in human-wildlife coexistence research

Human-wildlife interactions are situated within dynamic systems, characterized by social and ecological complexity. Human-wildlife coexistence research, however, typically focuses on one component of these systems in isolation. We inadvertently followed this norm while carrying out semi-structured interviews of livestock-owners in Northern Tanzania. As existing literature highlighted that this area was a hotspot for livestock depredation, our research questions focused on human interactions with carnivores. Interestingly, almost three quarters (72%, n = 72 of 100) of study participants independently raised African elephants (Loxodonta africana) as presenting the greatest impediments to coexistence. By centering our interviews on carnivores, we omitted vital components of this complex system. To counteract the effects of this oversimplification, we changed our intended analytical process after data collection. Instead of conducting a quantitative analysis of rates of livestock depredation and perceptions of risk posed by a suite of sympatric carnivores, we applied a grounded theory approach to assess interactions across multiple dimensions of this complex system. Through this transparent effort to realign our approaches with the complexity of the study system, we highlight the importance of designing research approaches that effectively reflect the complexities inherent to human-wildlife coexistence

A disrupted circumstellar torus inside eta Carinae's Homunculus Nebula

We present thermal infrared images of the bipolar nebula surrounding eta Carinae at six wavelengths from 4.8 to 24.5 microns. These were obtained with the MIRAC3 camera system at the Magellan Observatory. Our images reveal new intricate structure in the bright core of the nebula, allowing us to re-evaluate interpretations of morphology seen in images with lower resolution. Complex structures in the core might not arise from a pair of overlapping rings or a cool (110 K) and very massive dust torus, as has been suggested recently. Instead, it seems more likely that the arcs and compact knots comprise a warm (350 K) disrupted torus at the intersection of the larger polar lobes. Some of the arcs appear to break out of the inner core region, and may be associated with equatorial features seen in optical images. The torus could have been disrupted by a post-eruption stellar wind, or by ejecta from the Great Eruption itself if the torus existed before that event. Kinematic data are required to rule out either possibility.Comment: 8 pages, 3 figures (Fig. 1 in color); to appear in ApJ Letter